tbuckley/cabot-search huggingface dataset:
B-cell and complement signature in severe hidradenitis suppurativa that does not respond to adalimumab
Authors: Roisin Hambly, Solene Gatault, Conor M Smith, Luis F Iglesias-Martinez, Sean Kearns, Helen Rea, Vivien Marasigan, Kate Lynam-Loane, Shivashini Kirthi, Rosalind Hughes, Jean M Fletcher, Walter Kolch, Brian Kirby
Journal: British Journal of Dermatology (2022)

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder with significant morbidity. The pathogenesis remains incompletely understood although immune dysregulation plays an important role. It is challenging to treat and approximately 50% of patients respond clinically to adalimumab, the only licensed treatment.To examine differences between lesional and nonlesional HS skin at baseline using bulk RNA sequencing, and to compare the transcriptome in the skin before and after 12 weeks of treatment with adalimumab. To examine transcriptomic differences between adalimumab responders and nonresponders using Hidradenitis Suppurativa Clinical Response and the International Hidradenitis Suppurativa Severity Score System (IHS4); and to compare transcriptomic differences based on disease severity (Hurley stage and IHS4).We completed bulk RNA sequencing on lesional and nonlesional skin samples of patients before and after 12 weeks of treatment with adalimumab.Baseline differentially expressed genes and pathways between lesional and nonlesional skin highlighted chemokines and antimicrobial peptides produced by keratinocytes; B-cell function; T-cell-receptor, interleukin-17 and nuclear factor-κB signalling; and T-helper-cell differentiation. Transcriptomic differences were identified in lesional skin at baseline, between subsequent responders and nonresponders. Patients with severe HS who did not respond to adalimumab had enriched complement and B-cell activation pathways at baseline. In addition, logistic regression identified CCL28 in baseline lesional HS skin as a potential biomarker of treatment response.This highlights the potential for targeting B-cell and complement pathways in HS treatment and the potential of stratifying patients at baseline to the most suitable treatment based on the skin transcriptome. CCL28 has not previously been identified in HS skin and has potential clinical relevance due to its antimicrobial function and homing of B and T cells at epithelial surfaces. Our results provide data to inform future translational and clinical studies on therapeutics in HS.
Deficient mismatch repair is detected in large-to-giant congenital melanocytic naevi: providing new insight into aetiology and diagnosis
Authors: Boxuan Wei, Jieyu Gu, Bowen Gao, Yongyang Bao, Ran Duan, Qingfeng Li, Feng Xie
Journal: British Journal of Dermatology (2022)

Abstract Background The aetiologies of large-to-giant congenital melanocytic naevi (LGCMN) remain ambiguous. A previous study discovered signatures associated with deficient mismatch repair (dMMR) in patients with LGCMN. However, a screening diagnostic immunohistochemistry (IHC) panel of dMMR in patients with LGCMN has not been performed to date. Objectives To identify the MMR status and aetiologies of LGCMN. Methods A total of 110 patients with CMN, including 30 giant CMN, 30 large CMN, 30 medium CMN and 20 small CMN, underwent diagnostic IHC (for MSH6, MSH2, PMS2 and MLH1) screening of dMMR. The control group comprised normal skin samples from 20 healthy people. MMR proteins with little effect (MSH3 and PMS1) on the MMR system were stained in all samples. The surgical procedures conducted on each patient were noted because they might alter the behaviour of CMN and confound the results. Binary logistic regression analyses were performed between the phenotypic data and MMR status to identify associations. Whole-exome sequencing was performed on the main naevi, satellite naevi and normal skin tissues of four patients to detect variants. Mutational signature analyses were conducted to explore the aetiologies of LGCMN. Results dMMR was detected in 37% (11 of 30) of giant, 23% (7 of 30) of large and 7% (2 of 30) of medium CMNs, but were not identified in small CMNs or normal skin tissues. Moreover, multiple LGCMNs had a much higher dMMR rate than did single LGCMNs. The regression analyses showed that MMR status was significantly associated with CMN size and the presence of satellites, but was not correlated with age, sex, location, satellite diversity or tissue expansion. Notably, the pattern of protein loss in LGCMN mainly consisted of PMS2 loss. Mutational signature analyses detected dMMR-related signatures in patients with LGCMN. Additionally, rare deleterious germline mutations in DNA repair genes were detected in LGCMN, mainly in MSH6, ATM, RAD50, BRCA1 and ERCC8. These germline mutations were single-patient variants with unknown significance. Conclusions dMMR is one of the aetiologies underlying LGCMN, particularly in patients with giant main lesions and multiple satellite lesions. Further studies are necessary to investigate the role of the DNA repair system, particularly MMR, in LGCMN.
Variants in <i>KLK11</i>, affecting signal peptide cleavage of kallikrein-related peptidase 11, cause an autosomal-dominant cornification disorder
Authors: Zhuoqing Gong, Shangzhi Dai, Xingyuan Jiang, Mingyang Lee, Xuejun Zhu, Huijun Wang, Zhimiao Lin
Journal: British Journal of Dermatology (2022)

Mendelian disorders of cornification (MeDOC) are a group of heterogeneous genodermatoses with different genetic bases. The pathogenesis of a substantial group of MeDOC remains to be elucidated.To identify a new causative gene and the pathogenesis of a previously undescribed autosomal-dominant cornification disorder.Whole-exome sequencing was performed in three families with the novel cornification disorder to identify the disease-causing variants. As the variants were located around the signal peptide (SP) cleavage site of a kallikrein-related peptidase, SP cleavage, subcellular localization and extracellular secretion of the variants were evaluated in eukaryotic overexpression systems by Western blotting or immunocytochemistry. Then the trypsin-like and chymotrypsin-like proteolytic activity of the peptidase and degradation of its catalytic substrate were assayed using the patients' stratum corneum (SC) samples. The morphology of the lamellar bodies and corneodesmosomes (CDs) in the patients' SC was ultrastructurally examined. A mouse model harbouring the equivalent variant was constructed and evaluated histologically.We identified two heterozygous variants affecting Gly50 in kallikrein-related peptidase (KLK)11 in a familial case and two sporadic cases with the new disorder, which is characterized by early-onset ichthyosiform erythroderma or erythrokeratoderma. KLK11 belongs to the family of kallikrein-related peptidases participating in skin desquamation by decomposing CDs, a process essential for shedding of the SC. In vitro experiments demonstrated that the variants perturbed the SP cleavage of KLK11, leading to subcellular mislocalization and impaired extracellular secretion of the KLK11 Gly50Glu variant. Both trypsin-like and chymotrypsin-like proteolytic activities were significantly decreased in the patients' SC samples. Reduced proteolysis of desmoglein 1 and delayed degeneration of CDs were detected in patients' SC, indicating delayed skin desquamation. Consistently, the patients showed a thickened, dense SC, indicating abnormal skin desquamation. Mice harbouring the homozygous c.131G>A (p.Gly44Glu) Klk11 variant, which is equivalent to KLK11 c.149G>A (p.Gly50Glu) in humans, exhibited hyperkeratosis and abnormal desquamation, partially recapitulating the phenotype.We provide evidence that variants at Gly50 affecting the SP cleavage of KLK11 cause a new autosomal-dominant cornification disorder with abnormal desquamation. Our findings highlight the essential role of KLKs in maintaining homeostasis of skin keratinization and desquamation.
Bacillus Calmette–Guérin-induced lupus vulgaris in a patient with Mendelian susceptibility to mycobacterial disease caused by a novel <i>STAT1</i> variation
Authors: Aika Shionoya, Yuko Yoto, Tokimasa Hida, Aki Ishikawa, Tadashi Hasegawa, Takeshi Tsugawa, Hisashi Uhara
Journal: British Journal of Dermatology (2022)

We reported a case of BCG vaccination-induced lupus vulgaris in an 11-year-old girl with Mendelian susceptibility to mycobacterial disease (MSMD) due to a novel STAT1 gene variation. The dermatologists should suspect MSMD in patients with cutaneous tuberculosis after BCG vaccination. It prevents both the patients and the family members with inborn errors of immunity from receiving inadequate vaccines.
When too much is too much: noncoding duplications in skin disorders
Authors: Verónica Yumiceba, Malte Spielmann
Journal: British Journal of Dermatology (2022)

In the current issue of the British Journal of Dermatology, Liu &amp; Banka &amp; Huang et al report the first example of an inherited cancer predisposition syndrome caused by non-coding duplications on chromosome Xq26.1
Pathogenic variants in the <i>SPTLC1</i> gene cause hyperkeratosis lenticularis perstans
Authors: Sabine Jägle, Hao-Hsiang Hsu, Hazem A Juratli, Andreas D Zimmer, Amelie Prieschl, Svenja Alter, Bernhard Wiedenhofer, Dieter Metze, Steffen Emmert, Judith Fischer
Journal: British Journal of Dermatology (2022)

Hyperkeratosis lenticularis perstans (HLP), also known as Flegel disease, is a rare skin disease presenting with asymptomatic small hyperkeratotic papules. The lesions often appear on the dorsal feet and lower legs, and typically develop after the fourth decade of life. A genetic basis for HLP is suspected; however, so far no gene defect linked to the development of HLP has been identified.We aimed to identify the genetic cause of HLP.For mutational analysis we studied a cohort of five patients with HLP using next-generation sequencing (NGS). We used DNA -extracted from fresh skin biopsies alongside ethylenediamine tetraacetic acid (EDTA) blood samples from two patients, and formalin-fixed -paraffin-embedded skin biopsy material from three patients. In addition, immunofluorescence staining of HLP lesions from four patients was investigated.In all samples from the five patients with HLP we identified by NGS rare variants in the SPTLC1 gene. In four patients we detected small deletions/frameshift variants and in one patient a splicing variant, predicted to disturb the splicing process. In blood samples the detected variants were heterozygous with an allele frequency of 49% and 50%, respectively. In skin biopsies the allele frequency was within the range of 46-62%. Immunofluorescence staining revealed reduced SPTLC1 protein levels in skin of patients.Our findings suggest that pathogenic variants in the SPTLC1 gene are the underlying genetic cause of HLP. Of note, the identified variants were either frameshift- or splicing variants probably leading to nonsense-mediated mRNA decay and thus reduced SPTLC1 protein levels. We conclude that diminished SPTLC1, the key enzyme in sphingolipid biosynthesis, leads to the development of HLP, which highlights the sphingolipid pathway as a new therapeutic target.
Improving migrant health in the USA: opportunities for dermatologists to participate in care delivery, asylum medicine and community partnership
Authors: Penelope Kim-Lim, Herbert Castillo Valladares, Alexia Knapp, Coleen Kivlahan, Aileen Y Chang
Journal: British Journal of Dermatology (2022)

With an increase in migrant patients in the U.S. who are facing legal and health barriers, dermatologists can engage in opportunities to improve migrant health. These include: providing trauma-informed, culturally competent dermatologic care to migrants; partnering with human rights clinics to provide dermatologic consultations for asylum seekers with skin conditions or unique scars; and engaging with community organizations to collaborate and advocate for the health and well-being of migrants.
The perspectives of 606 US dermatologists on active surveillance for low-risk basal cell carcinoma
Authors: Sven van Egmond, Isabella de Vere Hunt, Zhuo Ran Cai, Nada Rizk, Marlies Wakkee, Mary-Margaret Chren, Noah Goldfarb, Julia F Simard, Eleni Linos
Journal: British Journal of Dermatology (2022)

In this survey study of over 600 US dermatologists, identical clinical scenarios (10mm primary asymptomatic BCC) were presented except for randomly varied patient characteristics including age, life expectancy, and tumor location. Most dermatologists (62%) recommended active surveillance for patients with advanced age (91 years) and a 1-year life expectancy. The odds ratio for choosing active surveillance was 20.31 (95% CI 14.10-35.30) comparing a patient with a 1-year life expectancy to a healthy patient.
Patient perspectives on the lived experience of granuloma annulare
Authors: Abigale Clark, Michael J Murphy, Brett King, Jeffrey M Cohen, Misha Rosenbach, John Barbieri, William Damsky
Journal: British Journal of Dermatology (2022)

Granuloma annulare is a relatively common inflammatory skin disease, yet patient-centered impacts of GA have not been thoroughly investigated, including the potential psychosocial and symptomatic burden, patients’ motivation for treatment, and patients’ perception of usefulness of commonly used medications. We conducted a survey of greater than 900 patients with GA and found an unexpectedly significant impact of GA on the quality of life, a generally poor reported response to commonly used therapies, and that symptoms such as itch and discomfort are not uncommon and may be the primary motivator for seeking treatment. More effective therapies and an understanding of their effect on quality of life is needed.
Quintuple Pregnancy
Authors: James N. Berbos, Bernard F. King, Albin Janusz
Journal: JAMA (1964)

There IS LITTLE agreement as to the incidence of multiple births among the many studies of their occurrence. This is not unexpected, however, since it has been postulated that the frequency of multiple births is influenced by a number of factors, among them the fertility of the people, which varies in different periods, multiparity, frequency of pregnancy, age of the mother, climate, race, and hereditary factors. Each study, then, can have significance only in terms of the specific population group examined; the results cannot be extended to a larger group and retain their validity. Table 1 provides an example of the wide variation in results of these studies. For practical purposes or, more precisely, for the purpose of the practicing physician, the formula devised by Hellin<sup>2</sup>is adequate, even though erroneous. He declared that the ratio of single births to twin births was about the same as that of
Mechanisms of drug resistance in HCC
Authors: Alexandra D. Ladd, Sergio Duarte, Ilyas Sahin, Ali Zarrinpar
Journal: Hepatology (2023)

HCC comprises ∼80% of primary liver cancer. HCC is the only major cancer for which death rates have not improved over the last 10 years. Most patients are diagnosed with advanced disease when surgical and locoregional treatments are not feasible or effective. Sorafenib, a multikinase inhibitor targeting cell growth and angiogenesis, was approved for advanced unresectable HCC in 2007. Since then, other multikinase inhibitors have been approved. Lenvatinib was found to be noninferior to sorafenib as a first-line agent. Regorafenib, cabozantinib, and ramucirumab were shown to prolong survival as second-line agents. Advances in immunotherapy for HCC have also added hope for patients, but their efficacy remains limited. A large proportion of patients with advanced HCC gain no long-term benefit from systemic therapy due to primary and acquired drug resistance, which, combined with its rising incidence, keeps HCC a highly fatal disease. This review summarizes mechanisms of primary and acquired resistance to therapy and includes methods for bypassing resistance. It addresses recent advancements in immunotherapy, provides new perspectives on the linkage between drug resistance and molecular etiology of HCC, and evaluates the role of the microbiome in drug resistance. It also discusses alterations in signaling pathways, dysregulation of apoptosis, modulations in the tumor microenvironment, involvement of cancer stem cells, changes in drug metabolism/transport, tumor hypoxia, DNA repair, and the role of microRNAs in drug resistance. Understanding the interplay among these factors will provide guidance on the development of new therapeutic strategies capable of improving patient outcomes.
Intrahepatic osteopontin signaling by CREBZF defines a checkpoint for steatosis-to-NASH progression
Authors: Fengguang Ma, Yuxiao Liu, Zhimin Hu, Yaqian Xue, Zhengshuai Liu, Genxiang Cai, Weitong Su, Zengpeng Zheng, Xia Fang, Xi Yan, Dong Ding, Xiaoyang Sun, Yang Jiang, Shuang Wei, Wenjing Li, Jiuxiang Zhao, Haibing Zhang, Hong Li, Dongguang Xiao, Cuiying Zhang, Hao Ying, Jun Qin, Xin Gao, Xiaozhen Dai, Wenguang Fu, Yong Xu, Yu Li, Aoyuan Cui
Journal: Hepatology (2023)

Background and Aims: NASH has emerged as a leading cause of chronic liver disease. However, the mechanisms that govern NASH fibrosis remain largely unknown. CREBZF is a CREB/ATF bZIP transcription factor that causes hepatic steatosis and metabolic defects in obesity. Approach and Results: Here, we show that CREBZF is a key mechanism of liver fibrosis checkpoint that promotes hepatocyte injury and exacerbates diet-induced NASH in mice. CREBZF deficiency attenuated liver injury, fibrosis, and inflammation in diet-induced mouse models of NASH. CREBZF increases HSC activation and fibrosis in a hepatocyte-autonomous manner by stimulating an extracellular matrix protein osteopontin, a key regulator of fibrosis. The inhibition of miR-6964-3p mediates CREBZF-induced production and secretion of osteopontin in hepatocytes. Adeno-associated virus –mediated rescue of osteopontin restored HSC activation, liver fibrosis, and NASH progression in CREBZF-deficient mice. Importantly, expression levels of CREBZF are increased in livers of diet-induced NASH mouse models and humans with NASH. Conclusions: Osteopontin signaling by CREBZF represents a previously unrecognized intrahepatic mechanism that triggers liver fibrosis and contributes to the severity of NASH.
Letter to the Editor: There may be a misunderstanding about the function of circular RNA as miRNA sponges
Authors: Chang Liu, Dan Liang
Journal: Hepatology (2023)

To the editor, We read with great interest the paper written by Xu et al.1. Xu et al.1 reported that a novel circular RNA (circRNA) located on chr17: 37880978–37882106 and looped by exons 23–26 of ERBB2 (circCCAC1), which was predicted as a potential prognostic marker and therapeutic target of cholangiocarcinoma. CircCCAC1 was significantly upregulated in CCA and acted as a molecular sponge of miR-514a-5p to promote the transcription factor Yin Yang 1 (YY1) expression. Moreover, YY1 could directly bind to the promoter of calcium-modulating ligand (CAMLG) to activate its transcription. We do not deny the research value of the manuscript. CircCCAC1/miR-514a-5p/YY1/CAMLG signal pathway will bring critical roles and potential promising clinical application value to those patients with CCA. However, the manuscript ignores the limited biological functions of most circRNAs as miRNA sponges, and the mechanism for whether circRNAs can act as miRNA sponges still deserves to be discussed and focused on. Guo et al.2 found that most circRNAs were expressed in only a few cell types and they are rarely cell type-specific. They also raised doubts regarding the biological function of most circRNAs. A sponge must have several miRNA-binding targets to be a "sponge."2 Therefore, only a few circRNAs can be recognized as miRNA sponges. Guo et al.2 also demonstrated that cerebellar degeneration-related protein 1 antisense RNA, which had over 70 selectively conserved miRNA-binding target sites to miR-7, was one of the best-known circRNAs and also a gene encoding zinc finger protein 91 was predicted to be the next miRNA-sponge candidate. The majority of circRNAs rarely contain multiple binding sites for the same miRNA, so the biological role of circRNAs as sponges for miRNAs may be limited.3–5 So the authors should further discuss the limited function of circRNAs as miRNA sponges in more depth in the future.
Circulating tumor nucleic acids: biology, release mechanisms, and clinical relevance
Authors: Pavel Stejskal, Hani Goodarzi, Josef Srovnal, Marián Hajdúch, Laura J. van ’t Veer, Mark Jesus M. Magbanua
Journal: Molecular Cancer (2023)

Despite advances in early detection and therapies, cancer is still one of the most common causes of death worldwide. Since each tumor is unique, there is a need to implement personalized care and develop robust tools for monitoring treatment response to assess drug efficacy and prevent disease relapse.
SARS-CoV-2 variant-related abnormalities detected by prenatal MRI: a prospective case–control study
Authors: Patric Kienast, Daniela Prayer, Julia Binder, Florian Prayer, Sabine Dekan, Eva Langthaler, Benjamin Sigl, Sabine Eichinger, Nicole Perkmann-Nagele, Ingrid Stuempflen, Marlene Stuempflen, Nawa Schirwani, Petra Pateisky, Christian Mitter, Gregor Kasprian
Journal: The Lancet Regional Health - Europe (2023)

There are known complications for fetuses after infection with SARS-CoV-2 during pregnancy. However, previous studies of SARS-CoV-2 in pregnancy have largely been limited to histopathologic studies of placentas and prenatal studies on the effects of different SARS-CoV-2 variants are scarce to date. To examine the effects of SARS-CoV-2 variants on the placenta and fetus, we investigated fetal and extra-fetal structures using prenatal MRI.For this prospective case-control study, two obstetric centers consecutively referred pregnant women for prenatal MRI after confirmed SARS-CoV-2 infection. Thirty-eight prenatal MRI examinations were included after confirmed infection with SARS-CoV-2 and matched 1:1 with 38 control cases with respect to sex, MRI field strength, and gestational age (average deviation 1.76 ± 1.65, median 1.5 days). Where available, the pathohistological examination and vaccination status of the placenta was included in the analysis. In prenatal MRI, the shape and thickness of the placenta, possible lobulation, and vascular lesions were quantified. Fetuses were scanned for organ or brain abnormalities.Of the 38 included cases after SARS-CoV-2 infection, 20/38 (52.6%) were infected with pre-Omicron variants and 18/38 (47.4%) with Omicron. Prenatal MRIs were performed on an average of 83 days (±42.9, median 80) days after the first positive PCR test. Both pre-Omicron (P = .008) and Omicron (P = .016) groups showed abnormalities in form of a globular placenta compared to control cases. In addition, placentas in the pre-Omicron group were significantly thickened (6.35, 95% CI .02-12.65, P = .048), and showed significantly more frequent lobules (P = .046), and hemorrhages (P = .002). Fetal growth restriction (FGR) was observed in 25% (n = 5/20, P = .017) in the pre-Omicron group.SARS-CoV-2 infections in pregnancy can lead to placental lesions based on vascular events, which can be well visualized on prenatal MRI. Pre-Omicron variants cause greater damage than Omicron sub-lineages in this regard.Vienna Science and Technology Fund.
Regulating Reproductive Medicine in a World without <i>Roe</i>
Authors: Kimberly Mutcherson
Journal: New England Journal of Medicine (2023)

Interview with Prof. Kimberly Mutcherson on the Dobbs v. Jackson Women's Health Organization decision and states' power to determine when life begins. (12:02)Download The real-world impact of Dobbs was immediate, but its consequences extend far beyond abortion care, as states gear up to expand protections for "potential life" without the limits imposed by Roe and Casey.